Stimulation patterns for treating dry eye

ABSTRACT

Described herein are electrical stimulation patterns and methods of use thereof for treating dry eye disease, tired eye, or other forms of ocular discomfort. The methods generally include applying patterned stimulation to an anatomical structure located in an ocular region or a nasal region to increase tear production.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/809,109, filed on Jul. 24, 2015, and titled “Stimulation Patterns forTreating Dry Eye,” which claims priority to U.S. Provisional PatentApplication No. 62/029,362, filed on Jul. 25, 2014, and titled“Stimulation Patterns,” and to U.S. Provisional Patent Application No.62/067,416, filed on Oct. 22, 2014, and titled “Stimulation Patterns,”each of which is incorporated by reference herein in its entirety.

FIELD

Described herein are electrical stimulation patterns and methods of usethereof for treating dry eye disease or tiredness of the eye. Themethods generally include applying patterned stimulation to ananatomical structure located in an ocular region or a nasal region. Theelectrical stimulation may elicit a reflex that activates the lacrimalgland or directly activate the lacrimal gland or nerves innervating thelacrimal gland to produce tears.

BACKGROUND

Dry Eye Disease (“DED”) is a condition that affects millions of peopleworldwide. More than 40 million people in North America have some formof dry eye, and many millions more suffer worldwide. DED results fromthe disruption of the natural tear film on the surface of the eye, andcan result in ocular discomfort, visual disturbance, and a reduction invision-related quality of life. Activities of daily living such asdriving, computer use, housework, and reading have also been shown to benegatively impacted by DED. Patients with severe cases of DED are atrisk for serious ocular health deficiencies such as corneal ulcerationand can experience a quality of life deficiency comparable to that ofmoderate-severe angina.

DED is progressive in nature, and generally results from insufficienttear coverage on the surface of the eye. This poor tear coverageprevents healthy gas exchange and nutrient transport for the ocularsurface, promotes cellular desiccation, and creates a poor refractivesurface for vision. Poor tear coverage typically results from: 1)insufficient aqueous tear production from the lacrimal glands (e.g.,secondary to post-menopausal hormonal deficiency, auto-immune disease,LASIK surgery, etc.), and/or 2) excessive evaporation of aqueous tearresulting from dysfunction of the meibomian glands. In turn, low tearvolume causes a hyperosmolar environment that induces inflammation ofthe ocular surface. This inflammatory response induces apoptosis ofsurface cells, which in turn prevents proper distribution of the tearfilm on the ocular surface so that any given tear volume is renderedless effective. A vicious cycle is initiated where more inflammation canensue and cause further surface cell damage, etc. Additionally, theneural control loop, which controls reflex tear activation, is disruptedbecause the sensory neurons in the surface of the eye are damaged. As aresult, fewer tears are secreted and a second vicious cycle developsthat results in further progression of the disease (fewer tears causenerve cell loss, which results in fewer tears, etc.).

There is a wide spectrum of treatments for DED, however, none providesadequate treatment of the condition. Treatment options include:artificial tear substitutes, ointments, gels, warm compresses,environmental modification, topical cyclosporine, omega-3 fatty acidsupplements, punctal plugs, and moisture chamber goggles. Patients withsevere disease may further be treated with punctal cautery, systemiccholinergic agonists, systemic anti-inflammatory agents, mucolyticagents, autologous serum tears, PROSE scleral contact lenses, andtarsorrhaphy. Despite these treatment options, DED continues to beconsidered one of the most poorly treated diseases in ophthalmology.Accordingly, it would be desirable to have a more effective treatmentfor dry eye.

SUMMARY

Described here are methods for treating one or more conditions (such asdry eye, tired eyes, reducing discomfort from wearing contact lenses,etc.) by providing electrical stimulation to an anatomical structurelocated in an ocular region or a nasal region. Exemplary anatomicalstructures include nerves, muscles, mucosal tissues, cutaneous sensorystructures such as Parcian corpuscles, Merkel cells, etc., within theseregions. The electrical stimulation, when delivered to certain targetsas described herein, is generally capable of initiating a reflex circuitthat activates the lacrimal gland to produce tears. The reflex circuitmay include stimulation of a nerve directly or a cutaneous sensory cellthat in turn activates a nerve which then produces either sensory inputto the brain, or motor input to a nerve that activates a muscle near,e.g., the eye, which in turn provides sensory input to the brain andinitiation of the reflex to activate the lacrimal gland. The electricalstimulation may additionally or alternatively be capable, when deliveredto other certain targets as described herein, of directly drivingefferent fibers innervating the lacrimal gland to produce tears.

More specifically, methods of generating lacrimation (tear production)by modifying parameters of electrical waveforms to generate afferent orefferent input are described. These methods generally optimize waveformsfor a sensed paresthesia, e.g., a sensation of tickle, twitch, and/orvibration in the eyelid and/or vicinity of the eyelid, eyebrow, as wellas the temporal and frontal area of the head. Experimentation by theinventors has found that these sensations are strongly associated withlacrimation.

Using the patterned stimulation waveforms disclosed herein, it isbelieved that sensory nerves are activated to send input to the brain toproduce lacrimation. Additionally or alternatively, the patternedstimulation waveforms may activate motor nerves that cause muscles inthe vicinity of the orbit, the nose, the mouth, and/or the frontal ortemporal face to vibrate in order to generate the sensation of tingle ortwitch or vibration as the effect, which initiates the reflex pathwayand thereby leads to lacrimation.

The electrical stimulation applied to the anatomical structuresgenerally includes a plurality of waveform parameters that define apatterned waveform. Delivery of the electrical stimulus may help totreat DED by inducing an increase in lacrimation, and may generate aparesthesia sensed by a patient. These patterned waveforms may becapable of increasing tear output as well as patient comfort duringand/or after application of the stimulation.

Implantable or hand-held devices may be employed when applying theelectrical stimulation. In some variations, the devices may comprise astimulator body and a stimulator probe, where the stimulator probecomprises one or more nasal insertion prongs, and wherein the stimulatorbody comprises a control subsystem to control a stimulus to be deliveredto the patient via the stimulator probe. In some of these variations,the stimulator probe comprises at least two nasal insertion prongs. Insome of these variations, the stimulator probe comprises at least oneelectrode. In other variations, the electrode comprises one or more ofplatinum, platinum-iridium, gold, or stainless steel. In somevariations, the stimulus is a biphasic pulse waveform. In some of thesevariations, the biphasic pulse waveform is symmetrical. In some of thesevariations, the frequency of the biphasic pulse waveform is between 30Hz and 80 Hz. In some variations, the stimulator probe is releasablyconnected to the stimulator body. In some variations, the stimulatorbody is reusable and the stimulator probe is disposable. In somevariations, the device further comprises a user interface. In some ofthese variations, the user interface comprises one or more operatingmechanisms to adjust one or more parameters of the stimulus.Additionally or alternatively, the user interface may comprise one ormore feedback elements.

In other variations, the devices may include an implantablemicrostimulator and an external controller. Exemplary implantabledevices that may be used to apply the electrical stimulation describedherein are disclosed in U.S. patent application Ser. No. 13/441,806,filed Apr. 6, 2012, and titled “Stimulation Devices and Methods,” whichis hereby incorporated by reference in its entirety. Exemplary hand-helddevices, as well as additional exemplary implantable devices, that maybe used to apply the electrical stimulation described herein aredisclosed in U.S. patent application Ser. No. 14/256,915, filed Apr. 18,2014, and titled “Nasal Stimulation Devices and Methods,” which ishereby incorporated by reference in its entirety.

In general, the methods disclosed herein include applying patternedelectrical stimulation to an anatomical structure in an ocular region ora nasal region to activate the lacrimal gland, where the patternedelectrical stimulation is defined by a plurality of waveform parameters,and increasing tear production using the patterned electricalstimulation. In some instances, the method further includes confirmingactivation of the lacrimal gland by evaluating a paresthesia sensed inthe ocular region or the nasal region.

The anatomical structure that is stimulated may be a nerve, cutaneoussensory cells (Parcian corpuscles, Merkel cells etc.), muscle, or tissuesuch as mucosa or sub-mucosa, in the ocular region or nasal region. Forexample, the anatomical structure may be the nasociliary nerve, theanterior or posterior ethmoid nerve, or the infra-trochlear nerve. Insome variations, the anatomical structure is a muscle in the ocularregion or the nasal region. In some variations, the anatomical structurecomprises a mucosal or sub-mucosal surface in the ocular region or thenasal region. In some instances, the anatomical structure may becutaneous sensory cells in the nasal or ocular glabrous skin, whichnaturally sense mechanical input such as pressure, vibration, tingle,temperature, or pain.

As further disclosed herein, the plurality of waveform parameters thatdefine the stimulation waveforms may be selected from the groupconsisting of on/off duration, frequency, pulse width, amplitude, andshape. Other suitable waveform parameters may also be used. For example,charge injection, which can be calculated by multiplying amplitude andpulse width, may be used as a waveform parameter. In some variations,the plurality of waveform parameters are selected from the groupconsisting of on/off duration, frequency, pulse width, amplitude, andshape. In some of these variations, the on/off duration ranges fromabout 0.1 to 5.0 seconds on, and about 0.1 to 5.0 seconds off. In someof these variations, the on/off duration is 1.0 second on, and 1.0second off. In some of these variations, the on/off duration is 5.0seconds on, and 5.0 seconds off. In some of these variations, thefrequency ranges from about 10 to 200 Hz. In some of these variations,the frequency ranges from about 30 to 150 Hz. In some of thesevariations, the frequency ranges from about 50 to 80 Hz. In somevariations, the frequency is 30 Hz. In some variations, the frequency is70 Hz. In some variations, the amplitude ranges from about 0.1 to 10 mA.In some of these variations, the maximum amplitude ranges from about 1to 3 mA. In some variations, the pulse width and amplitude generate awaveform having a triangular, rectangular, or square shape. In somevariations, the electrical stimulation is continuously applied. In othervariations, the electrical stimulation has on and off periods.

The combination of waveform parameters specific to a particularstimulation waveform, where at least one of the waveform parameters ismodulated over time, are referred to herein as “patterns” and theresulting stimulation waveform a “patterned waveform” or “patternedstimulation waveform.” The stimulation waveform optimized for aparticular patient to activate the lacrimal gland to produce tears andelicit a paresthesia in that patient is referred to herein as a“patient-optimized waveform.”

The patterned electrical stimulation may also be applied using astimulator comprising a plurality of patterned stimulation waveformsstored in memory. Selection of the patterned stimulation from theplurality of stored patterned stimulation waveforms may be random. Thepatterned stimulation waveforms may also be patient-optimized waveforms.

Systems for generating and applying the electrical stimulation waveformsare further disclosed herein. The systems may generally include one ormore stimulation electrodes and a controller, wherein the controllercomprises a programmable memory configured to store a plurality ofpatterned stimulation waveforms. The stimulation waveforms may or maynot be associated with a sensed paresthesia. The controller may also beconfigured to execute a program that cycles through a plurality ofwaveform parameter options. A user interface may be included andconfigured in a manner that allows the patient to select one or more ofthe stored plurality of patterned waveforms.

In some variations, the one or more stimulation electrodes areconfigured for implantation in an ocular region or a nasal region. Insome of these variations, the one or more stimulation electrodes areconfigured for placement on a mucosal surface or within sub-mucosaltissue. The one or more stimulation electrodes may also be configuredfor placement within a nasal cavity or a sinus cavity. In othervariations, the controller is configured for placement external to theocular region or the nasal region. In some variations, the patternedelectrical stimulation is applied by an electrode device disposed withina nasal cavity or a sinus cavity. In some variations, the patternedelectrical stimulation is applied by an electrode device implanted nearthe lacrimal gland. In some of variations, the systems are configuredfor activating cutaneous sensors or nerve fibers innervating cutaneoussensors in the mucosal surface or within sub-mucosal tissue. In somevariations, the systems are configured for activating cutaneous sensorsor nerve fibers innervating cutaneous sensors in tissue such as skin andmuscles of the ocular region, the forehead or the temple area of thehead.

In some variations, the patterned electrical stimulation is applied byan electrode device comprising a plurality of patterned stimulationwaveforms stored in memory. In some of these variations, the appliedpatterned stimulation is randomly selected from the plurality of storedpatterned stimulation waveforms. In some of these variations, theplurality of stored patterned stimulation waveforms arepatient-optimized waveforms. In some variations, the applied patternedstimulation is stored in memory as a patient-optimized waveform.

In some variations the systems described herein comprise one or morestimulation electrodes and a controller, wherein the controllercomprises a programmable memory configured to store a plurality ofpatterned stimulation waveforms associated with a sensed paresthesia. Insome variations, the one or more stimulation electrodes are configuredfor implantation in an ocular region or a nasal region. In some of thesevariations, the controller is configured for placement external to theocular region or the nasal region. In some variations, the one or morestimulation electrodes are configured for placement on a mucosal surfaceor within sub-mucosal tissue. In some variations, the one or morestimulation electrodes are configured for placement within a nasalcavity or a sinus cavity.

In some variations, the programmable memory is capable of storing up to10 patterned stimulation waveforms. In some variations the systemfurther comprising a user interface for selecting one or more of thestored plurality of patterned waveforms. In some variations, thecontroller is configured to execute a program that cycles through aplurality of waveform parameter options.

In some variations the methods described herein comprise applyingpatterned electrical stimulation to an anatomical structure in an ocularregion or a nasal region to activate the lacrimal gland, and increasingtear production using the patterned electrical stimulation, wherein thepatterned electrical stimulation comprises a biphasic waveform havingcathodic and anodic pulse pairs, each pulse having a duration andamplitude, wherein the ratio of duration to amplitude for each pulse isvariable over time. In some variations, the biphasic waveform is chargebalanced. In some of these variations, the ratio of duration toamplitude for the cathodic pulse varies over time according to afunction having a phase of increase according to an exponential functionand a phase of decrease according to an exponential function. In some ofthese variations, the ratio of duration to amplitude for the cathodicpulse varies over time according to a sawtooth function. In some ofthese variations, the ratio of duration to amplitude for the cathodicpulse varies over time according to a sinusoidal function.

In some variations the methods described herein comprise applyingpatterned electrical stimulation to an anatomical structure in an ocularregion or a nasal region to activate the lacrimal gland, and increasingtear production using the patterned electrical stimulation, wherein thepatterned electrical stimulation comprises a biphasic waveform havingcathodic and anodic pulse pairs, wherein a subset of the pulse pairshave a leading catholic pulse and a subset of the pulse pairs have aleading anodic pulse.

The frequency, peak-to-peak amplitude, and pulse width of the waveformsmay be constant, but in some variations the stimulator may be configuredto vary the frequency, amplitude, and/or pulse width of the waveform.This variation may occur according to a pre-determined plan, or may beconfigured to occur randomly within given parameters. For example, insome variations the waveform may be configured such that thepeak-to-peak amplitude of the waveform varies over time (e.g., accordingto a sinusoidal function having a beat frequency, a sawtoothed function,or an exponential function); in some variations the waveform may beconfigured such that the frequency of the waveform varies over time(e.g., according to a sinusoidal function, a sawtoothed function, or anexponential function); or in some variations the waveform may beconfigured such that the pulse width of the waveform varies over time(e.g., according to a sinusoidal function, a sawtoothed function, or anexponential function). In some variations, rectangular stimulationpulses of a variable fundamental frequency are employed. In othervariations, triangular stimulation pulses may be used and modulated asdescribed for rectangular stimulation pulses.

In some variations, the methods described herein comprise a method forinducing lacrimation. In some variations the method comprises deliveringan electrical stimulus to a patient having dry eye, wherein theelectrical stimulus is delivered from a handheld stimulator, and whereinthe electrical stimulus comprises a waveform having a pulse width thatvaries during delivery. In some variations the method comprisesdelivering an electrical stimulus to a patient having dry eye using ahandheld stimulator, wherein the electrical stimulus can be one of aplurality of preset waveforms comprising at least a first presetwaveform and a second preset waveform, and changing the electricalstimulus from the first preset waveform to the second preset waveformwhile delivering the electrical stimulus. The electrical stimulus may bechanged from the first preset waveform to the second preset waveform bythe patient.

In some variations, the methods described herein comprise providing adevice to a patient having dry eye, wherein the device is configured todeliver a plurality of electrical waveforms to an anatomical target in apatient, and instructing the patient to select one or more of theplurality of waveforms based on an amount of sensed paresthesia feltduring delivery of the waveform. In some of these variations, theanatomical target may be the nasal mucosa. In some of these variations,the anatomical target may be the anterior ethmoidal nerve. In others ofthese variations, the anatomical target may be in an ocular region. Insome of these variations, at least one of the plurality of waveforms mayhave a pulse width that varies over time. In some of these variations,the pulse width may vary over time according to an exponential function.

In some variations, the devices described herein comprise a handheldstimulator comprising a stimulator body comprising a user interface, anda stimulator probe comprising a nasal insertion prong comprising anelectrode. The stimulator may be configured to deliver a plurality ofelectrical waveforms, and the user interface may be configured forselection of one of the plurality of electrical waveforms. Each of thewaveforms may have at least one of a pulse shape, maximum amplitude,pulse width, or frequency that is modulated over time. In some of thesevariations, each of the waveforms has at least two of a pulse shape,maximum amplitude, pulse width, or frequency that is modulated overtime. In some variations, each of the waveforms has a pulse shape thatis modulated over time. In some variations, the waveform comprises afirst period comprising a two-phase current-controlled waveform, and asecond period comprising a current-controlled phase followed by avoltage-controlled phase.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a proposed pathway of action of sensory outputprocessed in various ganglia of the peripheral nervous system and nucleiof the central nervous system.

FIGS. 2A-2C depict an exemplary implantable microstimulator.

FIG. 3 depicts an exemplary external controller for an implantablemicrostimulator.

FIGS. 4A-4C depict an exemplary handheld stimulator.

FIGS. 5A-5C show exemplary waveforms.

FIGS. 6A-6D illustrate exemplary amplitude variations over time.

FIGS. 7A-7D illustrate exemplary pulse width variations over time.

FIG. 8 shows an exemplary function defining pulse widths increasing anddecaying according to an exponential function.

FIG. 9 shows a flowchart illustrating a method used in determining apatient-optimized waveform.

FIG. 10 illustrates exemplary shape modulation.

FIG. 11 illustrates exemplary pulse width modulation.

FIGS. 12A-12E illustrate exemplary modulations of amplitude andfrequency waveform parameters.

FIGS. 13A-13E depict exemplary waveforms showing multiple parametersthat are concurrently modulated over time.

FIG. 14A depicts paresthesia felt with stimulation applied at 30 Hz(non-patterned). FIG. 14B illustrates an exemplary moving paresthesiaobtained with waveform patterning. FIG. 14C illustrates anotherexemplary moving paresthesia obtained with waveform patterning. FIG. 14Ddepicts paresthesia felt by waveform patterning.

FIG. 15 is a bar-chart diagram comparing tearing results from basaltearing (left, no stimulation) to 30 Hz non-patterned waveformstimulation (middle) to patterned, patient-optimized stimulationwaveforms (right).

FIG. 16A shows bilateral Schirmer scores with no stimulation, 30 Hznon-patterned stimulation, and patient-specific patterned waveforms.FIG. 16B shows contralateral Schirmer scores with no stimulation, 30 Hznon-patterned stimulation, and patient-specific patterned waveforms.

FIGS. 17A-17B show bilateral responses to 30 Hz non-patternedstimulation (17A) and patient-specific patterned waveforms (17B).

FIG. 18 shows Schirmer scores for stimulation of left frontal nerveareas in rabbits.

DETAILED DESCRIPTION

Described herein are devices, systems, and methods for treating one ormore conditions (such as dry eye, tired eyes, ocular discomfort fromwearing contact lenses, etc.) by providing electrical stimulation to ananatomical structure located in an ocular region or a nasal region.Specifically, the methods disclosed herein generally include applyingpatterned electrical stimulation to an anatomical structure in an ocularregion or a nasal region to activate the lacrimal gland, where thepatterned electrical stimulation is defined by a plurality of waveformparameters. The electrical stimulation may result in effects such asincreased tear production during or after delivery of the stimulus.

In general, the methods disclosed herein include electricallystimulating nerves, muscles (thus indirectly nerves via muscle spindlesand golgi-tendon receptors providing sensory information back to thecentral nervous system), and/or glands in the orbit of the eye or thenasal mucosa and sub-mucosa. With that approach, neural tissue may beactivated in some manner. For example, referring to FIG. 1, theinventors hypothesize that the activation at an intra-nasal location 102or at an ocular location 104 causes action potentials to runantidromically and orthodromically from the activation point if theelectrode is activating the nerves directly, and orthodromically onafferent nerves if glands and muscles are activated to cause sensoryinput to the brain. Sensory input to the brain reaches the lacrimalnucleus in the pons, after passing several ganglia on the way, as shownby arrows 106, 108, 110, and 112. Here it is likely that neuralcomputation and data reduction happens in each of the ganglia as well asin the nuclei in the pons before the information is further relayed toareas of the sensory cortex in the cerebrum. Accordingly, the activationof neural tissue, directly or indirectly, may cause circuitry in thecentral nervous system (e.g., brain, spinal cord, potentially theganglia in the peripheral nervous system (PNS)) to respond to the input.Output from the brainstem 118 may then send feedback, as shown by arrow114, to the lacrimal gland.

The inventors found that some patients report that, after initiallynoticing a stimulation input, they do not feel the stimulation after afew (e.g., less than 30) seconds, even though the stimulation continuedto be delivered. The assessment was that the central nervous system musthave performed data reduction and thus facilitated accommodation inthese patients. Thus, the approach here is aimed at providing patientswith stimulation paradigms that reduced patient accommodation.

Exemplary Stimulators

The stimulation waveforms described herein may be delivered viaimplanted or non-implanted (e.g., handheld) stimulators.

Exemplary Implantable Microstimulators

When the stimulation waveforms described herein are applied using animplantable stimulator, the stimulator may comprise a microstimulatorcomprising a housing and a corresponding and complementary flexibleextension connected to the housing, forming a unitary microstimulator.An example is shown in FIGS. 2A-2C. As shown there, the microstimulator200 may comprise a housing 202 and a flexible extension 204 connected tothe housing 202. The housing 202 may be hermetically sealed, and maycontain some or all of the stimulation circuitry therein. Themicrostimulator 200 may comprise any stimulation circuits, such as thosedescribed in U.S. patent application Ser. No. 13/441,806, which waspreviously incorporated by reference in its entirety. The housing 202may be formed from one or more metals (e.g., titanium) or otherbiocompatible materials.

The extension 204 may be formed from a flexible material such assilicon, and may comprise a first electrode 206, a second electrode 208,and a coil 210. In some variations, the extension 204 may be a moldedcomponent, such as molded silicon. The extension may have acorresponding and complementary shape to the housing, such that theextension and housing together have a unitary shape, as shown in FIGS.2A-2B. The flexible extension 204 may conform to one or more portions ofthe anatomy (e.g., the orbit or the lacrimal gland) when implanted intissue. FIG. 2B shows a side view of the microstimulator 200. As shownthere, the thickness of the extension 204 may be less than that of thehousing 202, and may increase to the thickness of housing 202.Additionally, the width of the extension 204 is shown in FIG. 2A asbeing greater than the width of the housing 202, and may decrease to thethickness of the housing 202.

The electrodes 206 and 208 and coil 210 may be connected to themicrostimulator circuitry via one or more feedthroughs. For example,FIG. 2C shows a perspective view of the housing 202 with the extension204 removed. As shown there, housing 202 may comprise a plurality offeedthroughs 212 that extend through the housing 202. One or moreelements (e.g., one of the electrodes 206 or 208 or the coil 210) may beelectrically connected to the hermetically-sealed stimulation circuitryby connection to the feedthroughs 212. Additionally, some of thefeedthroughs 212 may comprise an insulating member 214 which mayelectrically isolate the feedthrough 212 from the housing 202. This andother implantable stimulators that may deliver the electrical stimulidescribed herein are described in U.S. patent application Ser. No.13/441,806, was previously incorporated by reference in its entirety;and in U.S. patent application Ser. No. 14/256,915, which was previouslyincorporated by reference in its entirety.

When the stimulator is an implantable microstimulator, the system mayfurther comprise a controller, which may communicate with themicrostimulator to transmit and/or receive power, information, or thelike. For example, in variations in which a stimulation system comprisesa microstimulator having a passive stimulation circuit (or a stimulationcircuit that does not otherwise include a battery or internal powersupply), the controller signal may power the stimulator via the outputsignal of the controller. The controller may communicate with themicrostimulator wirelessly and/or via a wired connection. The controllermay be configured for implantation within the body, or may be configuredto remain external to the body. The controller may be disposable, may bereusable, or may be partially reusable. In some instances, thecontroller may be rechargeable.

FIG. 3 depicts an exemplary external controller. As shown there, astimulation system 300 includes a controller 302 comprising a hand-helddevice. The controller 302 may be brought into the vicinity of animplanted microstimulator 306, and may produce an output signal 308received by the implanted microstimulator 306. The implantedmicrostimulator may in turn generate a stimulation signal 310 used tostimulate an anatomical target, as described in more detail herein. Thisand other controllers that may be used to deliver the electrical stimulidescribed herein are described in U.S. patent application Ser. No.13/441,806, which was previously incorporated by reference in itsentirety.

The length and width of the microstimulator may be selected to permitplacement of a portion of the microstimulator on, partially within orabout the lacrimal gland, or adjacent to a desired tissue, such as thelacrimal gland or a nerve desired to be stimulated, such as but notlimited to the nasociliary nerve or anterior ethmoidal nerve, asdescribed in more detail in U.S. patent application Ser. No. 13/441,806,was previously incorporated by reference in its entirety; in U.S. patentapplication Ser. No. 14/256,915, which was previously incorporated byreference in its entirety; and in U.S. patent application Ser. No.14/207,072, filed Mar. 12, 2014, and titled “Implant Delivery Devices,Systems, and Methods,” and which is hereby incorporated by reference inits entirety.

The microstimulator may be injectable into a patient using a deliverysystem. The delivery system may comprise an insertion device (such asconduit, a shaft to which the microstimulator is removably attachable,or the like) and/or a dissection tool. In some variations, the insertiondevice is a 12 or larger gauge needle. In other variations, theinsertion device comprises a cannula. In some variations, the insertiondevice may comprise a piston assembly, which in some variations may bespring-powered. The microstimulator may be loaded into the insertiondevice, and the insertion device may be inserted into an insertionpathway. In some variations in which the microstimulator is implantedinto an ocular region, using an anatomical landmark at the corner of theeye, a delivery device (e.g., a needle) may be positioned in proximityto the lacrimal gland, and the microstimulator may be deployed using thedelivery device. Anatomical landmarks include, but are not limited to,the lateral canthis, an eyelid margin, a palpebral lobe of the lacrimalgland, the orbital rim, a bony protuberance on the superior-lateralaspect of the orbit, the vascular bed, or the like. In some variations,a microstimulator may be implanted by lifting the eyelid, forming aninsertion pathway through the conjunctiva under the eyelid, andadvancing the microstimulator into the insertion pathway. The insertionpathway may be formed using a dissection tool. In some variations, theinsertion pathway may be formed using a dissection element of aninsertion tool. In some variations, the insertion pathway may be formedbetween the periosteum and the orbital bone. In other variations, theinsertion pathway may be formed between the periosteum and the lacrimalgland. The microstimulator may have one or more features to facilitateminimally invasive retrieval. U.S. patent application Ser. No.14/207,072, which was previously incorporated by reference in itsentirely, describes other variations of insertion devices that may beused to implant microstimulators described herein.

Exemplary Handheld Stimulators

FIGS. 4A-4C show perspective, cut-away back, and cut-away side views,respectively, of an illustrative variation of a handheld stimulator 400,respectively. As shown in FIGS. 4A-4C, the stimulator 400 may comprise astimulator body 402 and a stimulator probe 404. Generally, thestimulator body 402 may be configured to generate a stimulus, describedin more detail herein, that may be delivered to the patient. Thestimulator body 402 may comprise a front housing 438, back housing 440,and proximal housing 442, which may fit together to define a body cavity454. The body cavity 454 may contain a control subsystem 436 and a powersource 452, which together may generate and control the stimulus.

The stimulus may be delivered to a patient via the stimulator probe 404.In some variations the stimulator body 402 and stimulator probe 404 maybe reversibly attachable. Some or all of the stimulator 400 may bedisposable, and some or all of the stimulator 400 may be reusable. Forexample, in variations where the stimulator probe 404 is releasablyconnected to the stimulator body 402, the stimulator body 402 may bereusable, and the stimulator probe 404 may be disposable andperiodically replaced. In some of these variations, the device comprisesa disabling mechanism that prevents stimulus delivery to the patientwhen the stimulator probe is reconnected to the stimulator body afterbeing disconnected from the stimulator body. Additionally oralternatively, the device may comprise a lockout mechanism that preventsthe stimulator probe from being reconnected to the stimulator body afterbeing disconnected from the stimulator body. In some variations, thedevice further comprises a detachable protective cap.

The stimulator probe may comprise at least one nasal insertion prong,which may be configured to be at least partially inserted into the nasalcavity of a patient. In the handheld stimulator variation shown in FIGS.4A-4C, the stimulator probe 404 may comprise two nasal insertion prongs406 and 408. The nasal insertion prongs may be self-aligning wheninserted into the nostrils of the patient. The stimulator probe 404 mayfurther comprise ridges 420, which may allow the patient to more easilygrip the probe 404.

Each nasal insertion prong may comprise at least one electrode. As shownin FIGS. 4A-4C, the probe 404 may comprise a first electrode 410 onnasal insertion prong 406 and a second electrode 412 on nasal insertionprong 408. As shown in the cut-away view of the stimulator 400 in FIG.4B, the electrodes 410 and 412 may be connected to leads 430 and 432located within prongs 406 and 408, respectively. The leads 430 and 432may in turn be connected to connectors 422 and 424, respectively.Connectors 422 and 424 may extend through lumens 408 and 410 in theproximal housing 442, and may connect directly or indirectly to thecontrol subsystem 436 and power source 452. As such, the electricalstimulus may travel from the control subsystem 436 through theconnectors 422 and 424, through the leads 430 and 432, and through theelectrodes 410 and 412. In some variations, the electrode comprises ahydrogel, which is described in more detail in U.S. patent applicationSer. No. 14/630,471, filed Feb. 24, 2015, and titled “PolymerFormulation for Nasolacrimal Stimulation,” which is hereby incorporatedby reference in its entirety.

The stimulator body may comprise a user interface comprising one or moreoperating mechanisms to adjust one or more parameters of the stimulus,as described in more detail below. The operating mechanisms may provideinformation to the control subsystem, which may comprise a processor,memory, and/or stimulation subsystem. In some variations, the operatingmechanisms may comprise first and second buttons, as illustrated forexample in FIGS. 4A and 4C as 414 and 416. In some variations, pressingthe first button may turn on the stimulator and/or change the stimuluswaveform, while pressing the second button 416 may turn off thestimulator and/or change the stimulus waveform. Additionally oralternatively, the user interface may comprise one or more feedbackelements (e.g., based on light, sound, vibration, or the like). Asshown, the user feedback elements may comprise light-based indicators,shown in the variation of FIG. 4A as indicators 418, which may provideinformation to the user. This stimulator and other hand-held stimulatorsthat may deliver the electrical stimuli described herein are describedin U.S. patent application Ser. No. 14/256,915, which was previouslyincorporated by reference in its entirety.

Waveforms

The electrical stimulation waveforms delivered by the stimulatorsdescribed herein may be tailored for specific treatment regimens and/orspecific patients. It should be appreciated that the waveforms describedhere may be delivered via a multi-polar, such as bipolar, tripolar,quad-polar, or higher-polar configuration or a monopolar configurationwith distal return. The waveforms may be a sinusoidal, quasi-sinusoidal,square-wave, sawtooth, ramped, or triangular waveforms,truncated-versions thereof (e.g., where the waveform plateaus when acertain amplitude is reached), or the like.

As is described in more detail herein, when patterning of electricalstimulation waveforms is employed, waveform parameters such as theshape, the frequency, the amplitude, and the pulse width may bemodulated. The frequency, pulse-width, and/or amplitude of the waveformmay be modulated linearly, exponentially, as a sawtooth, a sinusoidalform, etc., or they may be modulated randomly. The stimulation can alsobe interrupted as part of the patterning. That is, the stimulation canbe in an on/off condition, e.g., for durations of 1 second on/1 secondoff, 5 seconds on/5 seconds off, etc. Modulation of the waveform shape(e.g., rectangular vs. triangular vs. exponential) in a rhythmic ornon-deterministic, non-rhythmic fashion may also be used. Thus, numerousvariations in waveform patterning can be achieved. It should beunderstood that combinations of these parameter changes over time in arepetitive manner may also be considered patterning. In some instances,random patterning may be employed. Patterning may help to preventpatient habituation to the applied stimulation (i.e., may help toprevent the patient response to the stimulation decreasing duringstimulation).

In some instances, it may be desirable to configure the stimulationwaveform to minimize side effects. In some instances, it may bedesirable to promote stimulation of larger-diameter nerves (e.g.,afferent fibers of the trigeminal nerve), which may promote atherapeutic effect, while reducing the stimulation of smaller nerves(e.g., a-delta fibers, c fibers, sympathetic and parasympatheticfibers), which may result in pain, discomfort, or mucus production.Generally, for smaller pulse-widths, the activation threshold forlarger-diameter nerves may be lower than the activation threshold forthe smaller nerve fibers. Conversely, for larger pulse-widths, theactivation threshold for larger-diameter nerves may be higher than theactivation threshold for the smaller nerve fibers. Accordingly, in someinstances, it may be desirable to select a pulse width that preferablyactuates the larger-diameter nerves. In some variations, the pulse widthmay be between 50 μs and about 1200 μs. As another example, certainwaveforms may minimize activation of the branches of the trigeminalnerve (e.g., CN V2) that travel to the teeth. These may includewaveforms ranging from 30 μs to 300 μs in pulse width, 10 Hz to 150 Hzin frequency, and 0.1 mA to 5 mA in amplitude.

The stimulation may be delivered periodically at regular or irregularintervals. Stimulation bursts may be delivered periodically at regularor irregular intervals. The stimulation amplitude, pulse width, orfrequency may be modified during the course of stimulation. For example,the stimulation amplitude may be ramped from a low amplitude to a higheramplitude over a period of time. In other variations, the stimulationamplitude may be ramped from a high amplitude to a lower amplitude overa period of time. The stimulation pulse width may also be ramped from alow pulse width to a higher pulse width over a period of time. Thestimulation pulse width may be ramped from a high pulse width to a lowerpulse width over a period of time. The ramp period may be between 1second and 15 minutes. Alternatively, the ramp period may be between 5seconds and 30 seconds.

The patterned stimulation waveforms described herein may be used toincrease the comfort of the patient and/or may be used to improve theefficacy of the stimulation, and thus, described below are waveformparameters that may be used alone or in combination to increase comfortand/or efficacy.

Shape

In some instances, the waveform shape or modulation thereof may affectthe comfort and/or efficacy of the stimulation. When the stimulator(electrode device) is configured to create a pulse-based electricalwaveform, the pulses may be any suitable pulses (e.g., a square pulse, ahaversine pulse, or the like). The pulses delivered by these waveformsmay by biphasic, alternating monophasic, or monophasic, or the like.When a pulse is biphasic, the pulse may include a pair of single phaseportions having opposite polarities (e.g., a first phase and acharge-balancing phase having an opposite polarity of the first phase).Each phase of the biphasic pulse may be either voltage-controlled orcurrent-controlled. In some variations, both the first phase and thecharge-balancing phase of the biphasic pulse may be current-controlled.In other variations, both the first phase and the charge-balancing phaseof the biphasic pulse may be voltage-controlled. In still othervariations, the first phase of the biphasic pulse may becurrent-controlled, and the second phase of the biphasic pulse may bevoltage-controlled, or vice-versa. In some instances, a combination ofcurrent-controlled bilateral stimulation and voltage-controlled chargebalancing may allow for unilateral stimulation, and by modifying thewaveform shape, may allow for switching between areas of stimulation,e.g., between nostrils when electrodes are located in each nostril, asdescribed herein.

In some variations in which the waveform comprises a biphasic pulse, itmay be desirable to configure the biphasic pulse to be charge-balanced,so that the net charge delivered by the biphasic pulse is approximatelyzero. In some variations, a biphasic pulse may be symmetric, such thatthe first phase and the charge-balancing phase have the same pulse widthand amplitude. Having a symmetric biphasic pulse may allow the same typeof stimulus to be delivered, e.g., to each nasal cavity. The pulses of afirst phase may stimulate a first side of the nose (while providing acharge-balancing phase to a second side of the nose), while the pulsesof the opposite phase may stimulate the second side of the nose (whileproviding a charge-balancing phase to the first side of the nose).

In other variations in which the waveform comprises a biphasic pulse, abiphasic pulse may be asymmetric, where the amplitude and/or pulse widthof the first pulse may differ from that of the charge-balancing phase.Even if the biphasic pulse is asymmetric, the biphasic pulse may becharge-balanced. For example, the cathodic pulse may have loweramplitude but longer duration than the anodic pulse, or the cathodicpulse may have higher amplitude but shorter duration than the anodicpulse. In both instances, the charge injection (amplitude timesduration) may be equal for each pulse, such that the net chargedelivered by the biphasic pulse is approximately zero.

The shape of the waveform may be changed to preferentially activate thetissue near an electrode. For example, FIGS. 5A-5C illustrate exemplarywaveforms configured to preferentially activate tissue near one of twoelectrodes, and where the preferential activation may move from near oneelectrode to the other over time. In variations in which the stimulatoris a handheld stimulator configured to have an electrode in eachnostril, for example, this preferential activation may allow forpreferential activation of tissue in one of the two nostrils, which maychange over time. For example, FIG. 5A shows a variation of a biphasiccharge-balanced waveform 518 in which the aspect ratios(amplitude:duration) of the pulses changes over time. Shown there is awaveform that has a first pattern wherein a leading cathodic pulse has agreater amplitude and shorter duration in comparison to the followinganodic pulse. This pattern is found in the time periods indicated by 510and 514. The waveform has a second pattern where the leading cathodicpulse has a lesser amplitude and longer duration in comparison to thefollowing anodic pulse. This pattern is found in the time periodsindicated by 512 and 516. It should be appreciated that each time periodmay have any suitable duration and thus comprise any suitable number ofpulses. As one example, each time period may last for about 1 second. Inother examples, each time period may last for less than 1 second, about1 to about 5 seconds, about 5 to about 10 seconds, about 10 to about 20seconds, or longer.

In some variations the waveform may transition between two aspect ratiosin an abrupt fashion. In other variations the transition may be gradual,where the aspect ratio of the cathodic pulse may increase over time andthen decrease over time, while the aspect ratio of the anodic pulse maydecrease over time and then increase over time. FIG. 5B shows an exampleof a waveform 520 that gradually transitions between aspect ratios.These increases and decreases may have any suitable form, such as linearincreases and decreases or sinusoidal increases and decreases. In othervariations, the transition may have a sawtooth shape, in which theaspect ratio of the cathodic pulse increases gradually over time whilethe aspect ratio of the anodic pulse decreases gradually over time, andthen the aspect ratio of the cathodic pulse decreases abruptly while theaspect ratio of the anodic pulse increases abruptly.

In some variations, the polarity is switched back and forth between apattern in which the cathodic pulse is first and a pattern in which theanodic pulse is first. For example, FIG. 5C shows an illustrativeversion of such a stimulation waveform 522. As shown there, the timeperiods indicated by 502 and 506 may have a cathodic pulse and then ananodic pulse, while the time periods indicated by 504 and 508 may havean anodic pulse and then a cathodic pulse. It should be appreciated thateach time period may have any suitable duration. As one example, eachtime period may last for about 1 second. In other examples, each timeperiod may last for less than 1 second, about 1-5 seconds, about 5-10seconds, about 10-20 seconds, or longer. In some variations, each timeperiod may last for a single pair of pulses, such that the stimulationwaveform comprises a repeating pattern of two anodic pulses and twocathodic pulses.

Although the patterns having variable amplitude:duration aspect ratiosmay have uniform charge injection, they may preferentially activate thetissue near one of the two electrodes. That is, when the leadingcathodic pulse has a greater amplitude and shorter duration than theanodic pulse, the waveform may preferentially activate tissue near acathodic electrode; when the leading cathodic pulse has a lesseramplitude and longer duration than the anodic pulse, the waveform maypreferentially activate tissue near an anodic electrode. Changing aspectratios and switching polarities as described herein may increase thelacrimation response. This may be because switching polarities leads tonon-linear addition of the stimuli as perceived by the central nervoussystem, as well as because switching polarities reduces a patient'saccommodation to the stimuli.

Frequency

In order to treat dry eye or otherwise produce a tearing response bystimulating tissue, the stimulators described herein may be configuredto generate one of more waveforms at frequencies suitable forstimulating targeted tissue (e.g., a nerve). The frequency may affectthe comfort and/or efficacy of the stimulation. Generally, the frequencyis preferably between about 0.1 Hz and about 200 Hz. In some of thesevariations, the frequency is preferably between about 10 Hz and about200 Hz. In some of these variations, the frequency is preferably betweenabout 30 Hz and about 150 Hz. In others of these variations, thefrequency is preferably between about 50 Hz and about 80 Hz. In othersof these variations, the frequency is preferably between about 30 Hz andabout 60 Hz. In some variations, the frequency may be about 1.5 Hz,about 10.25 Hz, about 70 Hz, about 150 Hz, about 25 Hz, about 27.5 Hz,about 30 Hz, about 32.5 Hz, about 35 Hz, about 37.5 Hz, about 40 Hz,about 42.5 Hz, about 45 Hz, about 47.5 Hz, about 50 Hz, about 52.5 Hz,about 55 Hz, about 57.5 Hz, about 60 Hz, about 62.5 Hz, or about 65 Hz.In some variations, high frequencies, such as those between about 145 Hzand about 155 Hz may be too high for each pulse to stimulate/activatethe target tissues. As a result, the stimulation may be interpreted bythe patient to have an element of randomness, which in turn may help toreduce patient habituation. The frequencies described herein may besuitable for stimulating the targeted tissue to initiate a reflexcircuit that activates the lacrimal gland to produce tears, and/orsuitable for directly driving efferent fibers innervating the lacrimalgland. In some instances, the frequency may be chosen for preferentialactivation of certain anatomical targets, as described herein.

Amplitude

In order to treat dry eye or otherwise produce a tearing response bystimulating tissue, the stimulators described herein may be configuredto deliver a current suitable for stimulating targeted tissue (e.g., anerve). The maximum amplitude or modulation thereof may affect thecomfort and/or efficacy of the stimulation. When the stimulus comprisesa biphasic pulse and the first phase of the biphasic pulse iscurrent-controlled, the first phase may preferably have an amplitudebetween about 1.0 mA and about 10 mA. Amplitudes within these ranges maybe high enough to stimulate targeted tissue, but sufficiently low as toavoid any significant heating of tissue, ablation of tissue, or thelike. In some variations the amplitude may be between about 1.0 mA andabout 5.0 mA. In other variations, the first phase may have an amplitudeof about 0.1 mA, about 0.2 mA, about 0.3 mA, about 0.4 mA, about 0.5 mA,about 0.6 mA, about 0.7 mA, about 0.8 mA, about 0.9 mA, or about 1.0 mA.In some variations, the amplitude may be variable. For example, theamplitude may vary between about 1.3 mA and about 1.5 mA, about 2.2 mAand about 2.5 mA, about 3.2 mA and about 3.7 mA, about 4.3 mA and about5.0 mA. When the first phase of a biphasic pulse is voltage-controlled,the first phase may preferably have an amplitude between about 10 mV andabout 100 V.

When a stimulator is configured to deliver a pulse-based waveform, insome variations, the amplitude of the pulses may be constant over time.In other variations, the amplitude of the pulses may vary over time.This may reduce patient accommodation. In some variations, the amplitudeof pulses may increase (linearly, exponentially, etc.) from a minimumvalue to a maximum value, drop to the minimum value, and repeat asnecessary. In some variations, the amplitude of the pulses may varyaccording to a sinusoidal profile. In another variation, as illustratedin FIG. 6A, the amplitude may periodically increase from a baselineamplitude (A) to a higher amplitude (B) for a single pulse. In yetanother variation, as illustrated in FIGS. 6B-6C, the amplitude of thepulses may follow a periodically increasing and decreasing patternbetween two lower amplitudes (A, B), and periodically increase to ahigher amplitude (C) for a single pulse (FIG. 6B) or for a plurality ofpulses (e.g., two pulses) (FIG. 6C). In yet another variation, asillustrated in FIG. 6D, a higher amplitude pulse (or pulses) may bepreceded by a brief pause (i.e., no current delivery). Each of thesetypes of amplitude modulation may be implemented alone or in combinationwith any other type of amplitude modulation, and may reduce patientaccommodation.

In some variations in which the amplitude varies over time, theamplitude may vary at a frequency suitable for reducing patientaccommodation or increasing patient comfort such as between about 0.1 Hzand about 5 Hz, between about 1 Hz and about 5 Hz, between about 1 Hzand 2 Hz, between about 2 Hz and 3 Hz, between about 3 Hz and 4 Hz, orabout 4 Hz and about 5 Hz. In some variation, the amplitude may vary ata frequency of about 1.0 Hz, about 1.1 Hz, about 1.2 Hz, about 1.3 Hz,about 1.4 Hz, about 1.5 Hz, about 1.6 Hz, about 1.7 Hz, about 1.8 Hz,about 1.9 Hz, about 2.0 Hz, about 2.1 Hz, about 2.2 Hz, about 2.3 Hz,about 2.4 Hz, about 2.5 Hz, about 2.6 Hz, about 2.7 Hz, about 2.8 Hz,about 2.9 Hz, about 3.0 Hz, about 3.1 Hz, about 3.2 Hz, about 3.3 Hzabout 3.4 Hz, about 3.5 Hz, about 3.6 Hz, about 3.7 Hz, about 3.8 Hz,about 3.9 Hz, or about 4.0 Hz. In other variations, the stimulationwaveform may be a modulated high frequency signal (e.g., sinusoidal),which may be modulated at a beat frequency of the ranges describedabove. In such variations, the carrier frequency may be between about100 Hz and about 100 kHz.

Pulse Width

In order to treat dry eye or otherwise produce a tearing response bystimulating tissue, the stimulators described herein may be configuredto deliver a waveform in which the first phase may preferably have apulse width between about 1 μs and about 10 ms. In some of thesevariations, the pulse width may be between about 10 μs and about 100 μs.In other variations, the pulse width may be between about 100 μs andabout 1 ms. In yet other variations, the pulse width may be betweenabout 0 μs and about 300 μs. In yet other variations, the pulse widthmay be between about 0 μs and 500 μs. As described above, it may bedesirable to select a pulse width that preferably actuateslarger-diameter nerves. In some variations, the pulse width may bebetween 50 μs and about 1200 μs. As another example, pulse widths of 30μs to 300 μs may minimize activation of the branches of the trigeminalnerve (e.g., CN V2) that travel to the teeth.

In some variations, the amplitude of the pulses may be constant overtime. In other variations, the pulse width may vary over time. Pulsewidth modulation over time may increase the efficacy and/or comfort ofthe stimulation. In some variations, the pulse width may increase(linearly, exponentially, etc.) from a minimum value to a maximum value,drop to the minimum value, and repeat as necessary. In some variations,the pulse width may vary according to a sinusoidal profile. In anothervariation, as illustrated in FIG. 7A, the pulse width may periodicallyincrease from a baseline pulse width (A) to a longer pulse width (B) fora single pulse. In yet another variation, as illustrated in FIGS. 7B-7C,the pulse width may follow a periodically increasing and decreasingpattern between two shorter pulse widths (A, B), and periodicallylengthen to a longer pulse width (C) for a single pulse (FIG. 7B) or fora plurality of pulses (e.g., two pulses) (FIG. 7C). In yet anothervariation, as illustrated in FIG. 7D, a longer pulse width pulse (orpulses) may be preceded by a brief pause (i.e., no current delivery).Each of these types of pulse width modulation may be implemented aloneor in combination with any other type of pulse width modulation. In anyform of pulse width modulation, the pulse width may vary at any suitablefrequency. In some variations the pulse width may vary at about 0.1 Hz,about 0.2 Hz, about 0.3 Hz, about 0.4 Hz, about 0.5 Hz, about 0.6 Hz,about 0.7 Hz, about 0.8 Hz, about 0.9 Hz, about 1 Hz, about 1.1 Hz,about 1.2 Hz, about 1.3 Hz, about 1.4 Hz, or about 1.5 Hz. In somevariations, modulation of the pulse width at a rate between about 0.5 Hzand 1 Hz may be desirable to increase patient comfort duringstimulation.

In some variations, the increase and decrease of pulse width may bedefined by a function implemented by the stimulator. For example, thepulse width may be defined by a function such that the pulse widthvaries exponentially. In one variation, the function defining pulsewidth may comprise two phases—a first phase during which the pulse widthof the leading pulse increases over time, and a second phase duringwhich the pulse width of the leading pulse decreases over time. Duringthe first phase, the pulse width of the leading pulse approaches themaximum pulse width according to an exponential function, where at timet, PW{t} is defined by the equation

${{PW}\left\{ t \right\}} = {\left( {{PW}_{\max} - {PW}_{\min}} \right)\left( {1 - e^{- {(\frac{t}{\tau})}}} \right)}$

where PW_(max) is the maximum allowed pulse width, PW_(min) is theminimum allowed pulse width, and τ is a time constant.

Once a predetermined amount of time has elapsed (a multiple of timeconstant τ), the pulse width modulation may enter the second phase.During the second phase, the pulse width of the leading pulseexponentially decays from its maximum value to a minimum value followingthe exponential equation

${{PW}\left\{ t \right\}} = {\left( {{PW}_{\max} - {PW}_{\min}} \right){\left( {1 - e^{- {(\frac{t}{\tau})}}} \right).}}$

After a predetermined amount of time has elapsed (a multiple of timeconstant τ), the pulse width modulation may re-enter the first phase,and the cycle may repeat. The pulse width of the secondary (chargebalancing) pulse is increased and decreased accordingly to retain chargefull balancing. PW_(max), PW_(min), and τ may have any suitable valuesto achieve the pulse widths described herein, but in one example thewaveform may have a PW_(max) of 300 μs, PW_(min) of 0 μs, and τ of ⅕ μs.In other variations, for example, PW_(max), may be about 100 μs, about200 μs, about 300 μs, about 400 μs, or about 500 μs; PW_(min) may beabout 0 μs, about 10 μs, about 50 μs, or about 100 μs; and τ may beabout ⅓ μs, about ¼ μs, about ⅕ μs, or about ⅙ μs. An exemplary functiondefining exponentially increasing and decaying pulse widths is shown inFIG. 8.

On/Off Periods

In some instances, the waveforms described herein may be delivered in acontinuous fashion, while in other instances, the waveforms may bedelivered in a non-continuous fashion having on periods and off periods,which may reduce patient accommodation. Exemplary on/off durationsinclude without limitation, 1 second on/1 second off, 1 second on/2seconds off, 2 seconds on/1 seconds off, 5 seconds on/5 seconds off, 0.2seconds on/0.8 seconds off, less than 1 second on/less than 10 secondsoff.

Exemplary Waveforms

It should be appreciated any of the above waveform parameters andvariations in parameters may be combined to generate a patternedwaveform as described herein, and these waveforms may be delivered byany of the stimulators described herein. For example, in variationswhere the waveform comprises a biphasic pulse, the biphasic pulse mayhave any suitable frequencies, pulse widths, and amplitudes. Thestimulation amplitude, pulse width, and frequency may be the same frompulse to pulse, or may vary over time, as described in more detailherein. Combinations of these parameters may increase the efficacyand/or comfort of stimulation, and in some cases, the efficacy and/orcomfort may differ by individual patient, as described in more detailherein. Exemplary patterned waveform parameters categorized by devicetype are listed below in Table 1.

TABLE 1 Exemplary Waveform Parameters Waveform Parameters DeviceStimulation Frequency Pulse Width Amplitude Type Target On/Off (Hz) (PW)(mA) Ocular Orbital nerves Constant on 30 Fixed from 0.1 to 10Stimulator (afferent & 1 sec on/ 30 50 μs to 1200 μs (implantable)efferent) 1 sec off 5 sec on/ 30 5 sec off 1 sec on/ 70 1 sec off 1 secon/ 155 1 sec off Constant on Modulated from 30 to 70 in triangularfashion Constant on 30 Triangular modulated from 50 μs to max PW at 0.5Hz Constant on 30 Triangular modulated from 50 μs to max PW at 1 HzConstant on 70 Triangular modulated from 50 μs to max PW at 0.5 Hz NasalInternal and Constant on 30 0 μs to 300 μs 0.1 to 10 Stimulator externalnasal Constant on 50 (handheld or nerves Constant on 80 implantable)(e.g., anterior Constant on 150 ethmoidal nerve) 1 sec on/ 30 1 sec off1 sec on/ 50 1 sec off 1 sec on/ 80 1 sec off Constant on 30 1 sec on/70 1 sec off

In variations in which a waveform is an alternating monophasic pulsedwaveform, each pulse delivered by the stimulator may have a singlephase, and successive pulses may have alternating polarities. Generally,the alternating monophasic pulses are delivered in pairs at a givenfrequency (such as one or more of the frequencies listed above, such asbetween 30 Hz and 80 Hz), and may have an inter-pulse interval betweenthe first and second pulse of the pair (e.g., about 100 μs, between 50μs and 150 μs or the like). Each pulse may be current-controlled orvoltage-controlled, and consecutive pulses need not be bothcurrent-controlled or both voltage-controlled. In some variations wherethe pulse waveform is charged-balanced, the waveform may comprise apassive charge-balancing phase after delivery of a pair of monophasicpulses, which may allow the waveform to compensate for chargedifferences between the pulses.

When a stimulator configured to deliver an electrical stimulationwaveform is positioned to place an electrode on either side of the nasalseptum, alternating monophasic pulses may promote bilateral stimulationof nasal tissue. The pulses of a first phase may stimulate a first sideof the nose (while providing a charge-balancing phase to a second sideof the nose), while the pulses of the opposite phase may stimulate thesecond side of the nose (while providing a charge-balancing phase to thefirst side of the nose), since nerves may respond differently to anodicand cathodic pulses. The inter-pulse interval may give time for thestimulation provided by a first phase pulse to activate/polarize thetarget nerves prior to being reversed by an opposite phase pulse.

Patient-Optimized Waveforms

Experimentation by the inventors has found that in some instances,lacrimation caused by stimulation using patterned waveforms may beincreased by identification of one or more patient-optimized waveformsfor a particular patient, where the patient-optimized waveforms maycomprise combinations of the waveform parameters described herein. Assuch, a method for identification of patient-optimized waveforms isdesirable. Experimentation by the inventors has also found that sensedparesthesia is strongly associated with lacrimation, and thus patientperceptions of paresthesia may be used in identification ofpatient-optimized waveforms. An exemplary method for obtainingpatient-optimized waveforms in a patient having a microstimulatorimplanted in an ocular region is illustrated in FIG. 9. It may bedesirable to perform this method for each individual to increase theeffectiveness of stimulation (e.g., to increase tearing).

As shown there, a waveform may be assessed to determine if it is apatient-optimized waveform by delivering an electrical stimuluscomprising the waveform to the patient using a stimulator describedherein. The method may comprise first delivering a waveform at thelowest amplitude and/or pulse width and asking the patient for feedbackon the sensation as the amplitude and/or pulse width is increased. Themethod may then comprise assessing whether the patient feels anysensation during delivery of the electrical stimulus. If not, adifferent waveform may be selected (e.g., having a different combinationof parameters, such as frequency, amplitude, pulse width, on/off period,or the temporal modulation of these parameters). The method may furthercomprise ensuring that the patient is not experiencing discomfort. Ifthe patient is experiencing discomfort, the method may be restarted witha new waveform, or the amplitude and/or the pulse width may be reducedto alleviate discomfort. Similarly, the method may comprise ensuringthat the sensation during application of the waveform is comfortable tothe patient. The amplitude and/or pulse width may be adjusted to achievepatient comfort. Comfort may be assessed with the patient's eyes bothopen and closed.

A waveform may be designated as a patient-optimized waveform if thepatient perceives the waveform as the most comfortable and/or effectivewaveform felt that day; and/or if the patient feels his/her eyes gettingwet; and/or if the patient perceives paresthesia—more particularly, ifboth a tickle and a vibration are perceived as moving in the eyelid. Ifthe patient perceives a tickle in the eyelid but no vibration, theamplitude and/or pulse width may be adjusted to achieve increasedperception of tickle and/or vibration. If the patient perceives avibration but not tickle, the amplitude and/or pulse width may beadjusted to achieve an increased sensation of movement of the vibration(e.g., between the eyelid and eyebrow). It may also be desirable that apatient feels a sensation (e.g., tickle or vibration) after delivery ofthe stimulus ends. In each case of an identified patient-optimizedwaveform, a lower amplitude and/or pulse width may be tested todetermine whether the same sensation can be achieved using a loweramplitude and/or pulse width.

While the method in FIG. 9 is described with respect to a patient havingan implantable stimulator located in an ocular region, it should beappreciated that a similar method may be used to identify one or morepatient-optimized waveforms for an implantable stimulator in anotherregion (e.g., a nasal region) or for a handheld stimulator. Once apatient-optimized waveform or waveforms are identified, a stimulator maybe configured to deliver the waveform(s). In some variations, anexternal device may be used to configure the stimulator to deliver theidentified waveform(s). In variations in which the system comprises acontroller for use with an implantable stimulator having a passivestimulation circuit, a controller configured to generate an outputsignal that results in the identified stimulation waveform(s) may beused.

Devices Having a Plurality of Waveforms

Some variations of the stimulators described herein may be configuredwith a plurality of waveforms, such that a clinician and/or patient mayselect a desired waveform from the plurality of available waveforms. Forexample, the stimulator may include a plurality of stimulation waveformssaved on a chip. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than10 stimulation waveforms may be saved on a chip. In one variation, twoto ten stimulation waveforms are saved on a chip. In other variations,two to eight stimulation waveforms, or three to five stimulationwaveforms may be saved on the device chip. In some variations, apreferred set of waveforms to be saved on a stimulator may bepreselected by a clinician based on initial testing of a variety ofstimulation waveforms for a particular patient, such as via the methoddescribed above. It may be useful for the saved stimulation waveforms tobe those that elicit strong paresthesia in the patient, becauseexperimentation by the inventors has found that sensed paresthesia ismore strongly associated with lacrimation, as described herein. In othervariations, a stimulator may be preconfigured with a plurality ofstimulation waveforms not unique to an individual patient.

In some variations, for every stimulation provided during the day, adifferent waveform may be randomly selected from the saved plurality ofwaveforms. By randomly selecting a different waveform each time, therisk of patient developing tolerance to any particular stimulationpattern may be lowered. In another implementation, a multiplexor mightbe used to provide different combinations of internally saved waveformsto form a “quasi-non-repetitive” waveform when combining pieces fromdifferent repetitive waveforms. By multiplexing different waveforms toone combined waveform, habituation to the waveform can potentially belimited further.

In some variations, a patient may be able to selectively choose betweenthe plurality of stimulation waveforms saved on the stimulator, forexample, using a user interface such as a user interface as describedherein. In variations having such a user interface, the user interfacemay comprise one or more operating mechanisms, which may allow the user(i.e., the patient) to control the stimulation waveform. For example,the user interface may comprise one or more structures, such as but notlimited to a button, slider, lever, touch pad, knob, ordeformable/squeezable portion of the housing, which may allow the userto change the stimulation waveform.

The different waveforms may be configured such that a patient mayperceive them as spanning a range of intensities. In variations in whichthe stimulator is configured to deliver waveforms with different shapes,a patient may be able to change the tissue that is preferentiallystimulated by the waveform as described herein by selecting a waveformhaving a different shape (e.g., switching from a waveform having acathodic pulse first to a waveform having an anodic pulse first). Insome variations, when a patient turns on the stimulator for a second orsubsequent treatment period, the stimulator may initially turn on to awaveform selected previously by the patient (e.g., the waveform usedduring the previous treatment session, the most commonly used waveformduring a plurality of treatment sessions, etc.).

For example, in the instance where a handheld nasal stimulator isemployed, after the user has placed a portion of the stimulator incontact with the nasal tissue, the user may increase the perceivedintensity of the stimulus by changing between the plurality ofstimulation waveforms. It may be desirable for the patient to increasethe intensity of the stimulus until the stimulus causes preferredparesthesia (e.g., tingling, tickling, prickling) without causingdiscomfort. As such, the patient may be able to self-determine theproper stimulation intensity and self-adjust the stimulus to a waveformeffective to achieve the desired result (e.g., tear production). It maybe desirable for the user to increase the intensity of the stimulusslowly in order to minimize discomfort. Some patients might prefer theirsensation level to change over the course of time. They might want tostart with a strong sensation, followed by a weak sensation. They mightprefer to start with a weak sensation (e.g., light tickle) followed by astronger temporary sensation (e.g., light discomfort for a very shorttime). Some patients may be able to reduce a sensation of needing tosneeze during stimulation if strong and weak sensations are varied.

In one particular example, a stimulator may be configured to deliver aplurality of different waveforms each having a combination of one ormore of shape modulation, maximum amplitude modulation, pulse widthmodulation, and frequency modulation, as described herein. In someinstances, the stimulator may be stimulator 400 described above withrespect to FIGS. 4A-4C. In other instances, the stimulator may be themicrostimulator 200 described above with respect to FIG. 2A-2C.

One or more of the waveforms may have a pulse shape that is modulatedover time. In a variation illustrated in FIG. 10, the pulse shape may becycled between four periods. The first period may comprise a two-phasecurrent-controlled waveform with symmetrical phases. The second periodmay comprise a current-controlled first phase, followed by avoltage-controlled second phase. This may help to preferentiallystimulate a location closer to one electrode. The first phase may have acurrent sourced by a first electrode and sunk by a second electrode,while the second phase may have a current sourced by the secondelectrode and sunk by the first electrode. The third period may comprisea two-phase current-controlled waveform with symmetrical phases (i.e.,the third period may be the same as the first period). The fourth periodmay comprise a current-controlled first phase, followed by avoltage-controlled second phase. The first phase may have a currentsourced by the second electrode and sunk by the first electrode, whilethe second phase may have a current sourced by the first electrode andsunk by the second electrode. In each period, the pulses may becharged-balanced. The pulse shape may be modulated at any suitablefrequency, such as about 0.1 Hz.

One or more of the waveforms may have a pulse width that is modulatedover time. In one variation, the pulse width of the current-controlledphases may be modulated from 0 μs to 300 μs. The modulation may followan exponential function that describes the increase and decrease of thepulse width over time, as illustrated in FIG. 11 and as described inmore detail with respect to FIG. 8.

One or more of the waveforms may have a maximum amplitude that ismodulated over time. The amplitude modulation of the current-controlledphases may approximate a triangular shape, a rectangular shape, or anyother suitable shape. Exemplary amplitude modulations at variousfrequencies are illustrated in FIGS. 12A-12E, which show amplitudemodulations having a rectangular shape (FIG. 12B) and amplitudemodulations that approximate triangular shapes (12C-12E). The maximumamplitude may be modulated at any suitable frequency, such as betweenabout 0.5 Hz and about 3 Hz. It should be appreciated that in some othervariations, the maximum amplitude may be constant, as shown in FIG. 12A.

FIGS. 13A-13E depict exemplary waveforms 1310, 1320, 1330, 1340, and1350, respectively, wherein one or more of these parameters aremodulated over time, where each type of modulation is independent fromand concurrent with the other types of modulation. Boxes 1302, 1304, and1306 on FIG. 13E highlight modulation of shape, pulse width, and maximumamplitude, respectively. In some variations (e.g., those of FIGS.13B-13E) all three of shape, pulse width, and maximum amplitude aremodulated over time, but it should be appreciated that in othervariations of the waveform (e.g., that of FIG. 13A), only one or two ofthese parameters may be modulated over time.

The five waveforms of FIGS. 13A-13E may be available on the stimulator(e.g., stimulator 400 described above with respect to FIG. 4A-4C, ormicrostimulator 200 described above with respect to FIGS. 2A-2C), andthe stimulator may be configured such that the patient can use a userinterface (e.g., an interface comprising two buttons) to select betweenthe five different waveforms. In some variations of the device, when thedevice is used for a treatment period, turned off, and turned back onfor an additional treatment period, the device may automatically turn onto the last stimulation setting used.

Setting 1, illustrated in FIG. 13A, may have a stimulation frequency of30 Hz; a minimum stimulation current amplitude of 0.7 mA, a maximumstimulation current amplitude of 0.7 mA, and thus no variation inmaximum stimulation current amplitude (as shown in FIG. 12A); a minimumpulse width of 0 μs; a maximum pulse width of 300 μs; a pulse widthmodulation frequency of 1 Hz (rising and falling according to anexponential function, as shown in FIG. 11); a minimum charge injectionper phase (at 0 μs pulse width) of 0 μC; a maximum charge injection perphase (at 0.7 mA and 300 μs) of 0.21 μC; and a pulse shape that ismodulated as described above with respect to FIG. 10.

Setting 2, illustrated in FIG. 13B, may have a stimulation frequency of37.5 Hz; a minimum stimulation current amplitude of 1.33 mA, a maximumstimulation current amplitude of 1.5 mA, a variation in maximumstimulation current amplitude of 0.17 mA, and an amplitude modulationfrequency of 2.1 Hz (as shown in FIG. 12B); a minimum pulse width of 0μs; a maximum pulse width of 300 μs; a pulse width modulation frequencyof 1 Hz (rising and falling according to an exponential function, asshown in FIG. 11); a minimum charge injection per phase (at 0 μs pulsewidth) of 0 μC; a maximum charge injection per phase (at 1.5 mA and 300μs) of 0.45 μC; and a pulse shape that is modulated as described abovewith respect to FIG. 10.

Setting 3, illustrated in FIG. 13C, may have a stimulation frequency of45 Hz; a minimum stimulation current amplitude of 2.17 mA, a maximumstimulation current amplitude of 2.5 mA, a variation in maximumstimulation current amplitude of 0.33 mA, and an amplitude modulationfrequency of 2.6 Hz (as shown in FIG. 12C); a minimum pulse width of 0μs; a maximum pulse width of 300 μs; a pulse width modulation frequencyof 1 Hz (rising and falling according to an exponential function, asshown in FIG. 11); a minimum charge injection per phase (at 0 μs pulsewidth) of 0 μC; a maximum charge injection per phase (at 2.5 mA and 300μs) of 0.75 μC; and a pulse shape that is modulated as described abovewith respect to FIG. 10.

Setting 4, illustrated in FIG. 13D, may have a stimulation frequency of52.5 Hz; a minimum stimulation current amplitude of 3.2 mA, a maximumstimulation current amplitude of 3.7 mA, a variation in maximumstimulation current amplitude of 0.5 mA, and an amplitude modulationfrequency of 2.8 Hz (as shown in FIG. 12D); a minimum pulse width of 0μs; a maximum pulse width of 300 μs; a pulse width modulation frequencyof 1 Hz (rising and falling according to an exponential function, asshown in FIG. 11); a minimum charge injection per phase (at 0 μs pulsewidth) of 0 μC; a maximum charge injection per phase (at 3.7 mA and 300μs) of 1.11 μC; and a pulse shape that is modulated as described abovewith respect to FIG. 10.

Setting 5, illustrated in FIG. 13E, may have a stimulation frequency of60 Hz; a minimum stimulation current amplitude of 4.3 mA, a maximumstimulation current amplitude of 5.0 mA, a variation in maximumstimulation current amplitude of 0.67 mA, and an amplitude modulationfrequency of 2.5 Hz (as shown in FIG. 12E); a minimum pulse width of 0μs; a maximum pulse width of 300 μs; a pulse width modulation frequencyof 1 Hz (rising and falling according to an exponential function, asshown in FIG. 11); a minimum charge injection per phase (at 0 μs pulsewidth) of 0 μC; a maximum charge injection per phase (at 5.0 mA and 300μs) of 1.5 μC; and a pulse shape that is modulated as described abovewith respect to FIG. 10.

Through patterned waveforms having these parameter combinations, a largeparameter space may be provided on a single device with a simple userinterface and a limited number of settings. This may increase theability of a single device having a limited number of preset waveformsto deliver a waveform that is as effective or nearly as effective for anindividual patient as a waveform in which parameters are individuallytuned for each patient.

Anatomical Targets

In some variations, it may be desirable to deliver the electricalstimuli described herein to one or more nerves that innervate thelacrimal gland tissue. In some variations, it may be desirable todeliver the electrical stimuli described herein to the nasal mucosa.This may cause lacrimation by activating the nasolacrimal reflex. Insome instances, the targeted area may comprise tissue innervated by theanterior ethmoidal branch of the nasociliary nerve. In anothervariation, the anatomical structure is the posterior ethmoid nerve. Insome instances, the targeted area of the nasal mucosa may be superior tothe columella. In some of these instances, the targeted area may be nearthe inferior end of the nasal bone (i.e., near the interface between thenasal bone and the upper lateral cartilage). In other variations, thetargeted area may be the columella. In some variations, it may bedesirable to deliver the stimulus between about 20 mm and about 35 mminto the nasal cavity of the patient. In some of these variations, itmay be desirable to place an electrode between about 25 mm and about 35mm into the nasal cavity of the patient. It may be desirable that thestimulus be delivered in the anterior portion of the nasal cavity,within the nostrils and anterior to the turbinates, and in someinstances, at a location anterior to the middle turbinate, or at alocation anterior to the inferior turbinate. It may in some instances bedesirable to direct stimulus such that a portion is directed toward thefront of the nose. The stimulus may be delivered at least partiallythrough tissue of or near the septum. This may allow for selectiveactivation of nerves in the front of the septum (e.g., the ophthalmicbranch of the trigeminal nerve) while minimizing activation of nervestoward the rear of the nasal septum, which may reduce negative sideeffects that may occur from stimulation of nerves that innervate theteeth, and which may reduce rhinorrhea. It may also in some instances bedesirable to direct the stimulus so as to reduce negative side effectsthat may occur from stimulation of the olfactory area.

Other exemplary anatomical structures may include nerves, muscles,mucosal or sub-mucosal tissues (e.g., nasal or sinus mucosa orsub-mucosa), sensory cells in the glaborous and hairy skin, glands orother structures of a patient involved in the process of lacrimation orglandular vasodilation that may be electrically stimulated. For example,the anatomical structures may include, but are not limited to, alacrimal gland, one or more meibomian glands, lacrimal ducts, cutaneousreceptors (mechanoreceptors, Meissner's corpuscles, neurotendinousspindles, golgi tendon organs, Ruffini's corpuscles, Stretch Receptors,Ruffini corpuscle end-organs, Pacinian corpuscle end-organs, hairfollicle receptors, free nerve endings, thermoreceptors, bulboid orKrause corpuscles, nociceptors), parasympathetic nerves, fibers andneurites, sympathetic nerves, fibers and neurites, rami lacrimales,lacrimal nerve, perivascular nerves of lacrimal artery and branchesthereof, nerve fibers innervating the meibomian glands, myoepithelialcells of the lacrimal gland, acinar cells of the lacrimal gland, ductalcells of the lacrimal gland. In yet a further variation, the anatomicalstructure is the infra-trochlear nerve. In other variations, theanatomical structure is a cutaneous receptor responsible for sensingchanges in force or temperature over time or a set of cutaneousreceptors in an area of the skin reporting changes in force applied tothe skin directly or indirectly by moving hair growing in the skin, orthe nerves innervating the cutaneous receptors reporting changes inforce applied to the skin or hair in the skin, or temperature changes inthe skin including the mucosa, the sub-mucosa in the nose or theconjunctiva in the eye.

Stimuli comprising the waveforms described herein may be delivered tothese anatomical targets using stimulators such as those describedherein according to treatment regimens described in U.S. patentapplication Ser. No. 13/441,806, which was previously incorporated byreference in its entirety, and in U.S. patent application Ser. No.14/256,915, which was previously incorporated by reference in itsentirety.

Examples

The following examples further illustrate the electrical stimulationpatterns and their effects as disclosed herein, and should not beconstrued in any way as limiting their scope.

Example 1: Stimulation Using a Lacrimal Implant

Patients having microstimulators implanted in an ocular region weretested with 30 Hz non-patterned stimulation (control) and with on/offpatterns (1 second on/1 second off, 2 seconds on/2 seconds off, and 5seconds on/5 seconds off) at different frequencies (30 Hz, 70 Hz, and155 Hz). The implanted microstimulators had the features shown in FIGS.2A-2C and described herein.

Patient perception of the stimulus differed between the 30 Hznon-patterned waveform control and patterned waveforms. Specifically,whereas 3 patients receiving the 30 Hz non-patterned waveform felt thattheir perception of the waveform faded over the stimulation period, whenreceiving patterned waveforms, no patients reported perception of thewaveform fading over the stimulation period. When the stimulus was a 30Hz, 1 second on/off waveform (“Pattern 1”), 3 patients perceived thewaveform as continuous, while 15 perceived the waveform as intermittent.When the stimulus was a 30 Hz, 5 second on/off waveform (“Pattern 2”),all patients perceived the waveform as intermittent. When the stimuluswas a 70 Hz, 1 second on/off waveform (“Pattern 3”), 2 patientsperceived the waveform as continuous, and 10 perceived the waveform asintermittent. Patients reported that they perceived Pattern 3 as“stronger,” “faster,” and “sharper” than the other waveforms. When thestimulus was a 155 Hz, 1 second on/off waveform (“Pattern 4”), whetherpatients perceived the waveform as continuous or intermittent wasamplitude-dependent, and qualitative perceptions ranged, includingreports of the waveform as “weaker,” “strong,” or a “pinch.”

Moreover, patients reported a change in the quality and/or location ofparesthesia. FIG. 14A depicts the area 1402 of paresthesia felt withstimulation using the 30 Hz non-patterned waveform. With the patternedwaveforms, patients felt movement of the paresthesia (in the form ofvibration and/or tickle), as shown in FIG. 14B (the vibration and/or thetingle moved along their eyelid in the directions of the arrows 1404).Some patients felt continuously present vibration in one area 1408 andcontinuously present or partially appearing and reappearing sensation ortickle in other areas 1406, as shown in FIG. 14C. Other patientsexperienced an increase in affected area with paresthesia with patternedwaveforms, shown in FIG. 14D as area 1410 extending along one or both ofthe eyebrows and/or along or in the nose.

Patient perceptions after cessation of stimulation also differed betweenthe 30 Hz non-patterned waveform and the patterned waveforms. Whereaspatients did not perceive paresthesia after cessation of the control,patients reported perceiving paresthesia in the form of a tinglingsensation after cessation of Patterns 1, 3, and 4.

Schirmer scores increased with patterned waveforms as compared to the 30Hz non-patterned waveform control. With Pattern 1, one third of patientshad Schirmer scores that increased by 50%. With Pattern 3, threequarters of patients had Schirmer scores that increased by 50-100%. WithPattern 4, three eighths of patients had Schirmer scores that increasedby 100% or more.

Some of the patterned waveforms also provided additional advantages. Forexample, Pattern 1 used less power than the control while also reducingpatient accommodation; and Pattern 4 allowed for both nerve stimulationand block.

Example 2: Stimulation Using a Lacrimal Implant (2)

In patients having a microstimulator implanted in an ocular region, useof patterned waveforms generated an increase in lacrimation as measuredby Schirmer's test in comparison to basal tearing (control 1=no electricstimulation) and in comparison to stimulation at 30 Hz (non-patterned)(control 2). The implanted microstimulators had the features shown inFIGS. 2A-2C and described herein. The data is provided below in Table 2,and a bar-chart diagram comparing averaged tearing results from basaltearing (left, no stimulation) to 30 Hz non-patterned waveformstimulation (middle) to patterned, patient-optimized stimulationwaveforms (right) is shown in FIG. 15. Based on the data in Table 2, theaveraged value for basal tearing was 4.71 mm, the averaged value was4.96 mm for non-patterned stimulation at 30 Hz, and the average valuewas 8.29 mm when patterned stimulation was used. Overall, the increasein average Schirmer score using non-patterned stimulation at 30 Hz wasabout 5% as compared to basal tearing, and the increase in averageSchirmer score using patterned waveforms was about 76% as compared tobasal tearing. Thus, patient-optimized pattered waveforms were able toincrease tearing by a much greater amount (in this case, over 70percentage points) than a 30 Hz non-patterned waveform.

TABLE 2 Schirmer Scores from 12 Patients. 30 Hz Non- Basal PatternedPatterned Schirmer Schimer Schirmer Implanted Score (mm) Score (mm)Score (mm) Side L R Ave L R Ave L R Ave Patterned Waveform R 8 5 6.5 3 43.5 8 5 6.5 30 Hz amplitude modulated by about 30% L 3 8 5.5 3 5 4 5 86.5 70 Hz amplitude modulated by about 30% L 3 2 2.5 3 5 4 3 8 5.5 70 Hz1 sec on, 1 sec off L 2 3 2.5 5 5 5 5 3 4 70 Hz amplitude modulated byabout 30% L 12 18 15 10 9 9.5 13 19 16 30 Hz amplitude modulated by 100%L 4 3 3.5 6 6 6 7 7 7 70 Hz amplitude modulated by about 30% R 2 3 2.5 33 3 8 7 7.5 30 Hz 1 sec on, 1 sec off L 5 7 6 5 5 5 8 8 8 70 Hz 1 secon, 1 sec off L 2 2 2 2 1 1.5 5 5 5 70 Hz amplitude modulated by about30% R 4 2 3 12 6 9 18 12 15 30 Hz 5 sec on, 5 sec off L 4 2 3 7 2 4.5 77 7 30 Hz 1 sec on, 1 sec off L 4 5 4.5 5 4 4.5 7 16 11.5frequency-modulated 30 Hz to 70 Hz randomized

The patterned waveforms were also capable of generating paresthesia inpatients in whom paresthesia was not felt during stimulation or who onlyexperienced short-lived paresthesia (e.g., less than 30 seconds, oftenonly less than 10 seconds, of paresthesia felt even though stimulationwas supplied continuously). The newly acquired or re-acquiredparesthesia was further accompanied by increases in lacrimation andimproved patient satisfaction.

Patients often reported the feeling of vibration during stimulation andtingle during stimulation pauses (for example, during off portions ofwaveforms having a 1 second on/lsecond off pattern), and in certaincases for seconds or minutes after the stimulation had stopped afterapplication. There were several reports of patients feeling that thevibration or the tingle moved physically along their eyelid and eyebrow,in two cases even in their nasal area (outside and/or inside the nose).Patient reception was generally very positive.

Example 3: Stimulation Using a Lacrimal Implant (3)

Nineteen patients had microstimulators implanted in an ocular region.(Twelve of these patients are the same patients as in Example 2.) Foreach patient, a patient-optimized patterned waveform was determined bymodulating waveform frequency, pulse width, and on/off periods whilegathering patient feedback in order to maximize the reported paresthesiain the area of the orbit, as described above.

Each waveform was provided using the same controller/energizer for eachpatient. The waveforms tested for each patient included:

-   -   30 Hz    -   30 Hz, 1 second on, 1 second off    -   30 Hz, 5 seconds on, 5 seconds off    -   70 Hz, 1 second on, 1 second off    -   30 Hz, pulse-width modulated from 100% to 0% and back to 100% in        1 sec    -   30 Hz, pulse-width modulated from 100% to 70% and back to 100%        in 1 sec    -   70 Hz, pulse-width modulated from 100% to 70% and back to 100%        in 1 sec    -   frequency modulated from 30 Hz to 70 Hz in an approximately        linear fashion by steps of 5 Hz (i.e., for the increasing        portion of the frequency modulation, 30 Hz, 35 Hz, 40 Hz, 50 Hz,        55 Hz, 60 Hz, 65 Hz, 70 Hz), modulated up and down in 1 sec        (from 70 to 30 and back to 70 in one second)    -   frequency modulated from 30 Hz to 70 Hz in a random fashion,        with frequencies 5 Hz apart (30 Hz, 35 Hz, 40 Hz, 45 Hz, 55 Hz,        60 Hz, 65 Hz, 70 Hz)

Patients were asked a series of questions for each waveform, including:

-   -   whether the waveform was causing discomfort;    -   how they would compare the sensation from the waveform to other        waveforms, including 30 Hz non-patterned waveform, and any other        waveforms previously tested on the same day;    -   whether they had the sensation of their eyes getting wet;    -   whether they felt a combination of a tickle and vibration;    -   whether the sensation (tickle and/or vibration) felt as though        it was moving (this suggests less likelihood of accommodation);        and    -   the location of the sensation.

It was desirable that the patient feel sensation in the upper eyelid,since this was considered likely to correspond with activating thelacrimal and the frontal nerves in the orbit. The closer the sensationwas to the eye itself and the larger the area of paresthesia, the moreoptimal a waveform was rated. Additionally, waveforms that wereperceived as a mixture of tickle and vibration sensations in locationsthat corresponded with the sensory pathways of the ophthalmic branch ofthe trigeminal nerve (CN V1) were desirable. These locations includednot only the eyelid, but also the eyebrow, the temple area of theforehead, the nose (especially the inside of the nose), and certainareas of the forehead.

For each patient, three Schirmer scores were recorded: a basal Schirmerscore without any stimulation (“basal Schirmer”), an acute Schirmerscore during application of a 30 Hz non-patterned waveform (“30 HzSchirmer”), and an acute Schirmer score during application of thepatient-optimized patterned waveform for each patient (“patternedSchirmer”).

Average bilateral 30 Hz Schirmer scores and average bilateral patternedSchirmer scores were both higher than average bilateral basal Schirmerscores. Average bilateral patterned Schirmer scores were higher thanaverage bilateral 30 Hz Schirmer scores. Specific data for averagebilateral Schirmer scores are shown in FIG. 16A. As shown there, the 15patients with severe DED (defined as having basal Schirmer scores <10mm) averaged a 22% increase over basal Schirmer scores for 30 HzSchirmer scores and a 78% increase over basal Schirmer scores forpatterned Schirmer scores.

More patients showed increased bilateral Schirmer scores when stimulatedusing the patient-optimized patterned waveform than the 30 Hznon-patterned waveform. As shown in FIGS. 17A-17B, amongst the 15patients with severe DED, the number of non-responders decreased from47% (as shown in FIG. 17A) using the 30 Hz waveform to 20% (as shown inFIG. 17B) using the patient-optimized patterned waveform.

The comparison of ipsilateral (i.e., the eye on the same side as ocularimplant), contralateral (i.e., the eye opposite the ocular implant), andbilateral (i.e., the average of both eyes) Schirmer scores indicatedthat stimulation from a single ocular implant resulted in bilateral tearproduction, but the effect was more pronounced for patient-optimizedpatterned waveform stimulation. Ipsilateral 30 Hz Schirmer scores werefound to be higher than bilateral 30 Hz Schirmer scores, indicating that30 Hz stimulation resulted in more tear production in the ipsilateraleye than the contralateral eye; and conversely, contralateral 30 HzSchirmer scores were found to be lower than bilateral 30 Hz Schirmerscores, indicating that 30 Hz stimulation resulted in less tearproduction in the contralateral eye than the ipsilateral eye.

In contrast, both ipsilateral and contralateral patterned Schirmerscores were found to be similar to bilateral patterned Schirmer scores.This suggested that patterned stimulation better stimulated tearproduction in the contralateral eye than the 30 Hz stimulation, suchthat the patient-optimized patterned waveform was equally effective instimulating tear production in both the ipsilateral and contralateraleyes. It was hypothesized that this was a result of the reflexive drive(activated by stimulating the lacrimal and frontal nerves) adding to thedirect drive (lacrimal nerve only). FIG. 16B shows contralateralSchirmer scores for the 15 patients with severe DED. As shown there, thepatients averaged a 9% increase over basal Schirmer scores for 30 HzSchirmer scores and an 82% increase over basal Schirmer scores forpatterned Schirmer scores.

By switching frequencies, either linearly or randomly, patientsexperienced a mixture of vibration and tickle. By changing to the higherfrequency of 70 Hz at 1 second on/1 second off, modulating the frequency(30 to 70 Hz in 5 Hz increments), and/or changing the pulse width,specific patients reported the sense of tickle in addition to vibration,tickle alone or the impression of a moving vibration, often in thecombination with a moving sensation of tickle. It was also found thatstimulation with a patient-optimized patterned waveform allowed patientsto find the location for holding the energizers/controllers in order tocouple to the implant more quickly and repeatedly.

Example 4: Electrical Stimulation of the Nasal Mucosa

A patterned waveform was delivered to the nasal mucosa of subjects usinga device as described with respect to FIGS. 4A-4C. The patternedwaveforms delivered included the waveforms shown in FIGS. 13A-13E anddescribed herein, as well as waveforms at 30 Hz, 70 Hz, and 155 Hz withon/off periods of 1 second on/off and 5 seconds on/off. Tear output atthe same level as non-patterned stimulation was able to be achievedwhile reducing subject tendency to sneeze. Subjects also reported thefeeling of a nasal massage that was in most cases seen as improvedsensory impression. Subjects furthermore were able to use increasedstimulation amplitudes during nasal stimulation leading to increasedtearing without discomfort, as the maximal amplitude of charge used tostimulate was only applied for a short time. Subject reception wasgenerally very positive.

Example 5: Frontal Nerve Stimulation (Rabbit)

A rabbit was implanted with fine wire electrodes into its left frontalnerve area, and stimulation was applied at 30 Hz with amplitudes between0.1 mA and 5.0 mA. Stimulation and baseline measurements were repeated 3times each. As shown in Table 3 below and FIG. 18, while increasedlacrimation was observed with the 30 Hz (non-patterned) waveform, theincrease in lacrimation was more pronounced using a patternedstimulation with on and off periods of 10 seconds each, as measured bySchirmer scores taken during stimulus delivery.

TABLE 3 Patterned Baseline Waveform 30 Hz ST ST ST AVG DEV AVG DEV AVGDEV No Stim Right 5.5 0.7 7.8 0.4 5.3 3.2 Eye Stim Eye Left 5.0 1.4 16.52.8 9.0 2.8 Eye

1-8. (canceled) 9: A method of using a handheld system comprising one ormore stimulation electrodes and a control subsystem, wherein the controlsubsystem comprises a programmable memory storing a plurality ofpatterned stimulation waveforms, comprising: delivering at least one ofthe waveforms to nasal mucosa of a patient for a treatment period,wherein delivering the patterned stimulation waveform elicits aparesthesia sensation in the patient that is sustained throughout thetreatment period. 10: The method of claim 9, wherein the patient selectsone of the plurality of patterned stimulation waveforms for deliverybased on the intensity of the paresthesia sensation elicited. 11: Themethod of claim 9, wherein delivery of the waveform causes tearproduction. 12: The method of claim 9, wherein delivery of the waveformtreats dry eye. 13: The method of claim 9, wherein the treatment periodis at least 30 seconds. 14: The method of claim 9, wherein at least oneof the plurality of patterned stimulation waveforms comprises a pulseshape, maximum amplitude, and pulse width that are concurrentlymodulated over time. 15: The system of claim 14, wherein the pulse shapeis modulated at a frequency of 0.1 Hz. 16: The system of claim 14,wherein the maximum amplitude is modulated at a frequency between about0.5 Hz and about 3 Hz. 17: The system of claim 14, wherein the pulsewidth is modulated between 0 μs and 300 μs. 18: The method of claim 14,wherein the pulse width is modulated over time according to anexponential function.